AU666715B2

AU666715B2 - Heterocyclic compounds

Info

Publication number: AU666715B2
Application number: AU37108/93A
Authority: AU
Inventors: Michael Klaus; Peter Mohr
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 1992-05-07
Filing date: 1993-04-22
Publication date: 1996-02-22
Anticipated expiration: 2013-04-22
Also published as: AU3710893A; PH30350A; JPH069616A; CA2093577C; CN1041417C; ES2115691T3; US5391766A; NZ247523A; US5512683A; DE59308325D1; DK0568898T3; CA2093577A1; ATE164580T1; EP0568898B1; CN1080922A; EP0568898A1; JP2549239B2; ZA933083B

Abstract

Compounds of the formula <IMAGE> in which X represents -S-, -SO- or -SO2-; R<1> represents C7-10-alkyl or C7-10-alkoxy; R<2> represents a radical of the formula <IMAGE> R<3> represents carboxyl or lower alkoxycarbonyl; and n represents 1, 2 or 3; and salts of carboxylic acids of the formula I can be used as medicines, e.g. for the treatment of autoimmune disorders or disorders having a strong immunological component, such as psoriasis.

Description

P/03/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): Address for Service: Invention Title: F Hoffmann-La Roche AG 124 Grenzachsrstrasse CH-4002 BASLE

SWITZERLAND

DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 Heterocyclic compounds The following statement is a full description of this invention, including the best method of performing it known to me:- 5020 RAN 4060/162 The present invention is concerned with novel heterocyclic compounds of the formula (CH2)n in which X represents -SO- or -SO2-;

R

1 represents C 7 10 -alkyl or C7-1_-alkoxy;

R

2 represents a residue of the formula R3 or (b)

R

3 represents carboxy or lower-alkoxycarbonyl; and n represents 1, 2 or 3; and salts of carboxylic acids of formula I.

The invention is also concerned with pharmaceutical preparations based on the compounds of formula I or their salts and with a process for the manufacture of the compounds I.

The term "lower" used herein denotes groups with up to 6 carbon atoms. Preferred lower groups contain 1-4 carbon atoms, such as, for Sexample, methyl, ethyl, isopropyl or 2-methylpropyl.

The terms C 7 -10-alkyl and C7-10-alkoxy denote alkyl and alkoxy groups with 7-10 carbon atoms, such as heptyl, octyl, nonyl and decyl.

A preferred group of compounds of formula I comprises those in which R 1 is heptyl, octyl, heptyloxy or octyloxy; R 3 is carboxyl and X 502.

The compounds of formula I can be obtained by Grn/22.2.93

A

I-

-2 a) reacting a compound of the formula with a compound of the formula

,COOR

B NN ~COOR wherein R is lower-alkyl and either A is a triphenyiphosphoniuimethyl group CH1 3

CH-P[Q]

3 +Y or dialkoxyphosphinylethyl group

CF

3

C;H-PO(OR)

2 and B is formyl; or A is acetyl and B is a triphenylmethyiphosphonium group -CH 2 p[Q 3y- or a dialkoxyphosphinylmethyl group -CH 2

-PO(OR)

2 and Q is phenyl; or by b) reacting a compound of the formula with a compound of the formula )zz

COOR

L 'M -3wherein either A' is a triphenylmethylphosphonium group CH 2 -P[Qb3Y or a dialkoxyphosphinylmethyl group -CH 2

-PO(OR)

2 and B' is formyl; or A' is formyl and B'is a triphenylmethylphosphonium group -CH2-P[O] 3

Y

or a dialkoxyphosphinylmethyl group -CH 2

PO(OR

2 and n, Q and R have the significance given above, to give a compound of formula I in which

R

3 is -COOR and, if desired, saponifying the ester group -COOR and isolating the carboxylic acid obtained as such or as a salt; and/or oxidizing a compound of formula I obtained in which X is to a compound of formula I in which X is -SO- or -SO 2 The reaction of the compound II with the compounds III or IV and the reaction of the compound V with the compound VI can be carried out according to methods which are known per se for the Wittig or Horner reaction.

S The reaction of compounds having triphenylphosphonium groups (Wittig reaction) can be effected in the presence of an acid-binding agent, e.g. a strong base such as e.g. butyllithium, sodium hydride or the sodium salt of dimethyl sulphoxide, but primarily in the presence of an ethylene oxide which is optionally substituted by lower alkyl, such as 1,2- :butylene oxide, optionally in a solvent, e.g. in an ether such as diethyl ether or tetrahydrofuran or in an aromatic hydrocarbon such as benzene, in a temperature range lying between room temperature and the boiling point of the reaction mixture.

Y ,referred to above, is an anion. Examples of anions Y in the 1 Witting reagent are Cl-, Br-, HSO 4 and tosylate.

The reaction of compounds having dialkoxyphosphinyl groups S 3 30 (Homer reaction) can be carried out in the presence of a base and, preferably, in the presence of an inert organic solvent, e.g. in the presence of sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxan or a 1,2-dimethoxyalkane, or also a sodium alcoholate in an alkanol, e.g. sodium methylate in methanol, in a temperature range lying between 00 and the boiling point of the reaction mixture.

L

-4- A thus-obtained carboxylic acid ester of formula I can be hydrolyzed in a manner known per se, e.g. by treatment with alkalis, especially by treatment with aqueous-alcoholic sodium or potassium hydroxide solution in a temperature range lying between room temperature and the boiling point of the reaction mixture.

The thus-obtained carboxylic acid of formula I can be isolated in a manner known per se as such or as a salt, e.g. as an alkali salt, especially as the Na or K salt.

A compound of formula I in which X stands for can be oxidized using methods known per se to a compound of formula I in which X stands for -SO- or -SO2. The oxidation can be carried out using oxidation agents such as periodates, e.g. NaI04, or using organic peracids such as m-chloroperbenzoic acid. About one equivalent of peracid is used in the oxidation using organic peracids in order to obtain a sulphoxide compound (X SO), whereas the use of two equivalents of peracid leads to sulphones (X SO 2 The compounds of formula I can be present as double bond isomers. They generally occur in the trans or all-trans form in the process. Cis isomers which may occur can be separated in a manner known per se where required.

The starting materials of formulae II-VI are known or can be prepared in analogy to the known compounds or according to methods described in the following Examples.

The compounds of formula I are retinoic acid a-receptor (RARareceptor) inhibitors. It has been found that the compounds of formula I suppress retinoid-induced malformations. The compounds of formula I can therefore be used for the prevention of teratogenic effects which can occur during the therapeutic use of retinoids.

Furthermore, the compounds of formula I can be used for the treatment and prevention of disease states which can be caused by an over-regulation of the RARa-receptor. There come into consideration in this connection autoimmune diseases or other disorders having a strong L I imunological component such as e.g. psoriasis or other dermatological conditions.

The compounds of formula I and their salts can be used in the form of pharmaceutical preparations.

The preparations for systemic use can be produced e.g. by adding a compound of formula I or a salt thereof as the active ingredient to nontoxic inert solid or liquid carriers which are usual in such preparations.

The preparations can be administered enterally, parenterally or topically. Preparations in the form of tablets, capsules, drag6es, syrups, suspensions, solutions and suppositories are e.g. suitable for enteral administration.

Preparations in the form of infusion or injections solutions are suitable for parenteral administration.

For enteral and parenteral administration the compounds of formula I can be administered to adults in amounts of about 1-100 mg, Spreferably 5-30 mg/day.

For topical use the active substances are conveniently used in the form of salves, tinctures, creams, solutions, lotions, sprays, 25 suspensions and the like. Salves and creams as well as solutions are preferred. These preparations designed for topical use can be produced by mixing the active ingredients with non-toxic, inert solid or liquid carriers which are suitable for topical treatment and which are usual in such preparations.

SFor topical use there are conveniently suitable about 0.1-5%, preferably solutions as well as about preferably 0.3-2%, salves or creams.

If desired, an antioxidant, e.g. tocopherol, N-methyly tocopheramine as well as butylated hydroxyanisole or butylated hydroxytoluene, can be admixed with the preparations.

-6- The following abbreviations are used in the Examples which follow and which illustrate the present invention in more detail: DM' dimethylformamide DMSO dimethyl sulphoxide THF tetrahydrofuran RT room temperature m.p. melting point i.v. in a vacuum EtOEt diethyl ether tBuOH tert.-butanol AcOEt ethyl acetate Example 1 a) 14.9 g of NaH, 50% in paraffin oil, were washed twice with pentane, dried in a water-jet vacuum and suspended in 60 ml of DMF.

A solution of 64.8 g of 3-heptyloxyphenol in 320 ml of DMF was added dropwise thereto while cooling with ice. After stirring at OOC for minutes a solution of 42.3 g of dimethyl-thiocarbamoyl chloride in 100 ml of DMF was slowly added dropwise to this reaction mixture and the mixture obtained was stirred at room temperature overnight.

Thereafter, it was poured on to ice-water, acidified with 6N hydrochloric acid and extracted with AcOEt. The organic phase was washed with 25 water, saturated NaHCO 3 solution and H 2 0, dried over sodium sulphate s o o and evaporated. After filtration of the crude product over a silica gel column (eluent hexane/AcOEt 4:1) there were obtained 86.7 g of 0-(3heptyloxyphenyl)dimethylthiocarbamate as a pale yellow oil.

b) 80 g of O-(3-heptyloxyphenyl)dimethylthiocarbamate in 20 g portions were heated to 2600C for 8 hours in a metal bath. The thusobtained S-(3-heptyloxyphenyl)dimethylthiocarbamate was used in the next step without further purification.

c) 10 g of LiA1H 4 were suspended in 200 ml of THF and treated dropwise at 0°C with a solution of 77 g of S-(3-heptyloxyphenyl)dimethylthiocarbamate in 200 ml of THF. After stirring at room temperature for 1 hour a solution of 46.5 g of 3,3-dimethylallyl bromide in 200 ml of THF was added dropwise thereto and the mixture was stirred for a further 45 m'nutes. The reaction mixture was subsequently poured into an ice-water/6N hydrochloric acid mixture and extracted with EtOEt. After washing, drying and evaporation there was obtained a dark oily crude product which, after filtration over a silica gel column (eluent hexane/AcOEt gave 64 g of heptyl m-[(3-methyl-2butenyl)thio]phenyl ether as a yellow oil.

d) 76.9 g of heptyl m-[(3-methyl-2-butenyl)thio]phenyl ether were dissolved in 1.5 1 of toluene, treated with 55 g of p-toluenesulphonic acid and heated on a water separator for 20 hours. The cooled reaction mixture was diluted with AcOEt, washed twice with dilute sodium bicarbonate solution and water, dried and evaporated. There was obtained a yellow oil which consisted of 3 parts of 7-(heptyloxy)-3,4dihydro-4,4-dimethyl-2H-l-benzothiopyran and of 1 part of 3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran. Column chromatography (silica gel, eluent hexane/l% AcOEt) gave 48.6 g of pure 7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-l-benzothiopyran as a pale yellow oil.

e) 4.8 ml of acetyl chloride were dissolved in 80 ml of methylene chloride and treated portionwise at OOC with 9.1 g of aluminium chloride. After stirring at 0OC for 30 minutes a solution of 20.7 g of 7- (heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran in 70 ml of methylene chloride was added dropwise thereto, the mixture was stirred at OOC for 2 hours, poured on to ice-water and extracted with ether.

After washing with water, drying and evaporation the crude product was recrystallized from hexane and there were obtained 15.5 g of 6acetyl-7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran in colourless crystals, m.p. 69-710C.

f) 14 g of 6-acetyl-7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1benzothiopyran were dissolved in 200 ml of chloroform and treated dropwise at OOC with a solution of 8.5 g of m-chloroperbenzoic acid in 120 ml of chloroform. After stirring at OOC for 2 hours a further 8.5 g of m-chloroperbenzoic acid in 120 ml of chloroform were added dropwise. The reaction mixture was stirred at OOC overnight, poured into ice-water/dilute sodium chloride solution and extracted with I I I I- I I -I- -8methylene chloride. The organic phase was washed twice with water, dried and evaporated. After filtration of the crude product over a silica gel column (eluent hexane/AcOEt 4:1) and recrystallization from AcOEt there were obtained 12.5 g of 7-(heptyloxy)-3,4-dihydro-4,4dimethyl-2H-1-benzothiopyran-6-yl methyl ketone 1,1-dioxide in colourless crystals, m.p. 92-930C.

g) 3 g of sodium hydride (50% in mineral oil) were washed twice with pentane, dried in a water-jet vacuum and suspended in 50 ml of abs.

DMSO. A solution of 19.3 g of diethyl (4-carbethoxybenzyl)phosphonate in 100 ml of abs. DMSO was slowly added dropwise thereto at room temperature. After stirring at room temperature for 2 hours the mixture was treated dropwise with a solution of 10.5 g of 7-(heptyloxy)- 3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl methyl ketone 1,1dioxide in 50 ml of abs. DMSO and the mixture obtained was stirred at 400C for a further 2 hours. After cooling the reaction mixture was poured on to ice-water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulphate and evaporated. The oily dark orange residue was filtered over a silica gel column (eluent hexane/AcOEt 2:1) and gave 13.5 g of ethyl p-[(E,Z)-2-[3',4'-dihydro-4',4'-dimethyl-7'-(heptyloxy)-2'H-1benzothiopyran-6'-yl]propenyl]benzoate 1',1'-dioxide as a yellow oil (E/Z ratio about 1:1).

Example 2 13.5 g of ethyl p-[(E,Z)-2-[3',4'-dihydro-4',4'-dimethyl-7'-(heptyloxy)- 2'H-1-benzothiopyran-6'-yl]propenyl]benzoate 1',1'-dioxide were dissolved in 250 ml of ethanol and treated with a solution of 14.6 g of potassium hydroxide in 100 ml of water. After stirring at 500C for 3 hours the reaction mixture was poured on to ice-water, acidified with 3N hydrochloric acid and extracted with AcOEt. The organic phase was washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate/hexane and gave 10.2 g of an E/Z mixture of the corresponding acids. By preparative HPLC (reverse phase, eluent hdxane/THF 9:1 0.1% acetic acid) there were obtained, after recrystallization from AcOEt/hexane, 4.1 g of dihydro-4',4'-dimethyl-7'-(heptyloxy)-2'H-1-benzothiopyran-6'- L_ 'A -9yl]propenyl]benzoic acid l',l'-dioxide in colourless crystals, m.p. 168- 1690C, as well as 5.2 g of p-[(Z)-2-[3',4'-dihydro-4',4'-dimethyl-7'- (heptyloxy)-2'H-l-benzothiopyran-6'-yl]propenyl]benzoic acid dioxide, m.p. 176-1780C.

The Z compound can be converted by irradiation in THF with a Hg high pressure lamp into a 1:1 mixture of the E/Z isomers from which further pure E compound can be obtained by preparative HPLC.

Example 3 a) 13.6 g of 6-acetyl-7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1benzothiopyran were dissolved in 270 ml of THF. 164 ml of a 1 molar solution of vinylmagnesium bromide in THF were added dropwise thereto at -150C and the mixture was stirred at room temperature overnight. The reaction mixture was subsequently poured into ice-cold saturated ammonium chloride solution, extracted with EtOEt, washed with water, dried and evaporated. There was obtained a yellow-brown oil which was immediately dissolved in 270 ml of acetonitrile and treated portionwise while stirring with 16.3 g of triphenylphosphine hydrobromide. After stirring the reaction mixture at 5000C for 2.5 hours it was evaporated and the residue was dissolved in 500 ml of ethanol and extracted repeatedly with hexane. The ethanolic solution was evaporated and the residue was dissolved in methylene chloride. After drying over sodium sulphate the solution was again evaporated and the foam-like residue was stirred with hexane for several hours, the crystalline precipitate which formed in the meanwhile was filtered off, washed with hexane and dried at 500C in a high vacuum. There were obtained 26.6 g of 3-[(E)-(7-heptyloxy-3,4-dihydro-4,4-dimethyl-2H-1benzothiopyran-6-yl)-2-butenyl]triphenylphosphonium bromide, m.p.

880C (decomposition).

b) 25 g of the phosphonium salt obtained in a) were dissolved in 250 ml of THF and treated dropwise at -20oC with 25 ml of butyllithium, 1.6 molar in hexane. After 15 minutes a solution of 6.3 g of ethyl formyl-crotonate in 30 ml of THF was added dropwise to the red-brown reaction mixture and the mixture obtained was stirred at room temperature for a further 45 minutes. It was then poured into 500 ml of 8 037002 220493 5010 a methanol/ water mixture extracted repeatedly with hexane, the non-aqueous phase was washed 3 times with water, dried and evaporated. The yellow oily residue was dissolved in 500 ml of acet imrile and, after the addition of 560 mg of triphenylphosphine, 6 t. eated with 28 ml of 0.125% solution of palladium(II) nitrate in acetonitrile. The mixture was heated tr 500C for 5 hours, subsequently i evaporated and the crude product was filtered over a short silica gel |j column (eluent hexane/l% AcOEt). There were obtained 1S.7 g of a !i yellow oil which consisted of a mixture of the corresponding (4Z, 6Z), I 10 (all-E) and (6Z) compound. The further separation was effected by Smedium pressure chromatography using Lobar finished columns (Merck) (eluent hexane/3% AcOEt) and gave 6.6 g of ethyl (all-E)-7-[7heptyloxy-3,4-dihydro-4,4-dimethyl-2H-l-benzothiopyran-6-yl]-3-methylocta-2,4,6-trienoate as a yellow oil.

I Example 4 S.500 mg of the (all-E) ethyl ester obtained in Example 3 were dissolved in 20 ml of ethanol and treated with a solution of 560 mg of 20 potassium hydroxide in 10 ml of water. After 3 hours at 50C the clear yellow solution was poured on to ice-water, acidified with cold 3N hydrochloric acid and extracted with AcOEt. After drying and evaporation the crude product was recrystallized from AcOEt/hexane and there were obtained 150 mg of (all-E)-7-[7-heptyloxy-3,4-dihydro-4,4dimethyl-2H-l-benzothiopyran-6-yl]-3-methyl-2,4,6-octatrienoic acid as yellow crystals, m.p. 158-1800C.

Example Oxidation of the (all-E) ethyl ester obtained in Example 3 with S"_s 1 equivalent of m-chloroperbenzoic acid at OOC in chloroform as the solvent gave ethyl (all-E)-7-[7-heptyloxy-1-oxo-3,4-dihydro-4,4-dimethyl- 2H-1-benzothiopyran-6-yl]-3-methyl-octa-2,4,6-trienoate as a yellow oil which was converted by hydrolysis in analogy to Example 4 into (all-E)-7- [7-heptyloxy-l-oxo-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl]-3methyl-octa-2,4,6-trienoic acid. Melting point 195-1970C (from AcOEt/hexane).

11- "xj :dju a V Ilr I U p :\wpdocs\grs\465748\jgs 11 Example 6 Oxidation of the (all-E) ethyl ester obtained according to Example 3 with 2.2 equivalents of m-chloroperbonzoic acid at OOC in chloroform gave, after recrystallization from hexane, ethyl (all-E)-7-[7'-(heptyloxy)- 3',4'-dcihydro-4',4'-dimethyl-2'H-1-benzothiopyran-6'-yl]-3-methyl-2,4,6octatrienoate l',l'-dioxide, m.p. 105-1070C. Hydrolysis of this compound in analogy to Example 4 gave, after recrystallization from AcOEt/hexane, (all-E)-7-[7'-(heptyloxy)-3',4'-dihydro-4',4'-dimethyl-2'H- 1-benzothiopyran-6'-yl)-3-methyl-2,4,6-octatrienic acid l',l'-dioxide, m.p.

140-1410C.

Example 7 a) A solution of 10 g of m-hydroxybenzaldehyde in 100 ml of DMF was Sadded dropwise at OOC to a suspension of 4 g of sodium hydride (50% in mineral oil) in 50 ml of DMF. The mixture was stirred at OOC for a further hour and subsequently a solution of 11.1 g of dimethylthiocarbamoyl chloride in 150 ml of DMF was added dropwise thereto. The mixture was stirred at room temperature overnight, poured on to ice-water, acidified with 6N hydrochloric acid and extracted with AcOEt. After drying the organic phase, evaporation and filtration Sof the crude product over a silica gel column (eluent hexane/AcOEt 3:1) there were obtained 10.2 g of O-(3-formylphenyl)dimethylthiocarbamate as a yellowish oil. This product was heated to 2300C for 8 hours under argon in a metal bath and gave, after filtration over a silica gel column (eluent hexane/AcOEt 4:1, then 1:1) and recrystallization from EtOEt at -780C, 7.3 g of S-(3-formylphenyl)dimethylthiocarbamate in golden yellow V crystals, m.p. 76-770C.

Sb) 13.2 g of n-heptyltriphenylphosphium bromide were suspended in 200 ml of THF and treated dropwise at -10oC with 30 ml of nbutyllithium, 1.6 molar in hexane. After stirring at 00C for 1 hour there was obtained a clear red soluti -n to which a solution of 6 g of S-(3formylphenyl)dimethylthiocarbamate in 100 ml of THF was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, poured into a methanol/ water mixture and extracted with hexane. The non-aqueous phase was washed repeatedly with water, I

R

/2 12dried and evaporated. After filtration over a silica gel column (eluent hexane/AcOEt 9:1) there were obtained 6.5 g of S-(3-(1-octenylphenyl)dimethyltbh:ocarbamate as a colourless oil (E/Z ratio about 3 g of this product were dissolved in 250 ml of glacial acetic acid and, after the addition of 6 g of platinum/charcoal hydrogenated at 800C/10 bar.

After 1 hour the hydrogenation was interrupted, the catalyst was filtered off and the filtrate was evaporated. After filtration over a silica gel column eluent hexane/AcOEt 9:1) there were obtained 2.4 g of S-(3octylphenyl)dimethylthiocarbamate as a colourless oil.

c) 0.4 g of lithium aluminium hydride was suspended in 25 ml of THF. A solution of 2.4 g of S-(3-octylphenyl)dimethylthiocarbamate in ml of THF was added dropwise thereto at 0oC and the mixture was stirred at 0OC for 2 hours. Subsequently, a solution of 1.2 g of 3,3dimethylallyl bromide in 10 ml of THF was added dropwise thereto and the mixture was stirred at OOC for a further 2 hours. The reaction mixture was poured on to ice-water, acidified with 6N hydrochloric acid, extracted with EtOEt, dried and evaporated. After filtration over a silica gel column (eluent hexane/AcOEt 4:1) there were obtained 2.3 g of 3octylphenyl (3-methyl-2-butenyl) thioether as a colourless oil. This product was dissolved in 100 ml of toluene and, after the addition of 2 g of p-toluenesulphonic acid, heated to reflux for 20 hours on a water separator. After cooling the reaction mixture was neutralized by the addition of aqueous sodium bicarbonate solution and extracted with AcOEt. After filtration over a silica gel column (eluent hexane/AcOEt S. 9:1) there were obtained 2.1 g of 7-octyl-3,4-dihydro-4,4-dimethyl-2H-1benzotJiiopyran as a pale yellowish oil.

d) 0.6 g of acetyl chloride was dissolved in 50 ml of methylene chloride and treated portionwise at 0OC with 1 g of aluminium chloride.

After 15 minutes a solution of 2.1 g of 7-octyl-3,4-dihydro-4,4-dimethyl- 2H-1-benzothiopyran in 50 ml of methylene chloride was added dropwise thereto. The mixture was stirred at 000C for 2 hours, poured on to icewater and extracted with methylene chloride. The crude produt was purified by chromatography on a Lobar finished column (Merck) (eluent hexane/AcOEt There were obtained 1.3 g of 6-acetyl-7-octyl-3,4dihydro-4,4-dimethyl-2H-1-benzothiopyran as a pale yellowish oil.

-13e) 1.3 g of 6-acetyl-7-octyl-3,4-dihydro-4,4-dimethyl-2H-1benzothiopyran were dissolved in 100 ml of chloroform. At OOC there were added dropwise thereto firstly 1 equivalent (0.74 g) of 85% mchloroperbenzoic acid dissolved in 50 ml of chloroform and after 2 hours a further equivalent of m-chloroperbenzoic acid. The mixture was stirred at OOC overnight, poured on to ice-water/sodium carbonate and extracted with methylene chloride. After recrystallization of t -rude product from AcOEt/hexane there was cbtained 1 g of 6-acetyl-'. cyl-3,4dihydro-4,4-dimethyl-2H-1-benzothiopyran-1,1-dioxide in colourless crystals, m.p. 77-780C.

f) In an analogy to Example 1 by reacting 0.95 g of 6-acetyl-7-octyl- 3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-1,1-dioxide with 1.8 g of diethyl (4-carbethoxybenzyl)phosphonate, after deprotornization with sodium hydride in dimethyl sulphoxide and flash chromatography of the crude product on silica gel (hexane/AcGEt there were isolated 1.3 g of ethyl 4-[2-(4,4-dimethyl-7-octyl-1,1-dioxo-3,4-dihydro-2H-1benzothiopyran-6-yl)-propenyl]-benzoate as a pale yellow oil with an E/Z ratio of about 4:9. The E/Z ratio can be shifted in favour of the E isomer (E/Z 1:1) by irradiating the crude product in THIF with a Hg high pressre lamp for 5 hours. By preparative HPLC (diisopropyl ether/hexane 55:45) of 0.9 g of E/Z mixture there were obtained 300 mg of the E isomer and 430 mg of the Z isomer as pale yellowish oils.

Example 8 300 mg of ethyl 4-[2-(4,4-dimethyl-7-octyl-1,1-dioxo-3,4-dihydro-2H- 1-benzothiopyran-6-yl)-propenyl-benzoate were dissolved in 30 ml of K -ethanol. After the addition of a solution of 330 mg of potassium 30 hydroxide in 10 ml of water the mixture was heated to 400C for 3 hours.

The clear reaction mixture was poured on to ice-water, acidified with 3N hydrochloric acid and repeatedly extracted with AcOEt. A'ter recrystallization of the crude product from AcOEt/hexane there were obtained 210 mg of (E)-4-[2-(4,4-dimethyl-7-octyl-1,1-dioxo-3,4-dihydro-2H- 3a 1-benzothiopyran-6-yl)-propenyll-benzoic acid in white crystals, m.p. 176- 1780C.

-c i 5020 -14- Example 9 1.84 g of 1-(1,1-dioxo-5,5-dimethyl-8-octyloxy-2,3,4,5-tetrahydro-1benzothiepin-7-yl)-ethanol were placed in 20 ml of acetonitrile and treated with 1.84 g of triphenylphosphine hydrobromide. The mixture was heated under reflux for 65 hours, cooled and evaporated i.v. The residue was taken up in CH 2 C12, dried over Na 2

SO

4 and again evaporated. Trituration in 100 ml of EtOEt/he:ane finally yielded 2.82 g of phosphonium salt as white crystals which were reacted as follows: The crystals are dissolved in 25 ml of abs. THF under argon and deprotonized at 0OC by the dropwise addition of 3.9 ml of 1.55M nBuLi (hexane). 814 mg of ethyl 4-formylbenzoate were added to the red ylid solution after 15 minutes and the mixture was left to react at 0OC for 1 hour and at room temperature for 1 hour. Extraction with AcOEt, washing with water, drying, evaporation, flash chromatography on S. silica gel (hexane/AcOEt 85/15) and three-fold recrystallization from hexane/AcOEt finally gave 702 mg of methyl (E)-4-[2-(8-octyloxy-5,5dimethyl-1,1-dioxo-2,3,4,5-tetrahydro- -benzothiepin-7-yl)-propenyl]benzoate as white crystals, m.p. 79-800C.

The 1-(1,1-dioxo-5,5-dimethyl-8-octyloxy-2,3,4,5-tetrahydro- 1benzothiepin-7-yl)-ethanol used as the starting material can be prepared as follows: a) 16.9 g of methoxymethyltriphenylphosphonium chloride were placed in 100 ml of abs. THF and treated slowly at -50C under argon with ml of 1.55M nBuLi. After 15 minutes a solution of 8.26 g of 8-bromo- 2,3,4,5-tetrahydro-1-benzothiepin-5-one in 50 ml of THF was slowly added dropwise and the mixture was left to react for 2 hours. Then, the reaction mixture was partitioned between hexane and EtOH/water 8/2, the lighter phase was dried and evaporated i.v. There were obtained 9.1 g of crude enol ether mixture which was hydrolyzed in 70 ml of THF under argon using 70 ml of 35% HC10 4 After 2 hours at room temperature the mixture was poured on to ice, washed with water, dried and evaporated. Flash chromatography on silica gel (hexane/AcOEt u wmcn C is heptyl, octyl, heptyloxy or octyloxy; R 3 is carboxyl and X

SO

2 The compounds of formula I can be obtained by Grn/22.2.93 95/5) gave 6.86 g of 8-bromo-2,3,4,5-tetrahydro-l-benzothiepine-5carbaldehyde as a colourless oil (91.5% pure according to GC).

b) 6.86 g of the aldehyde obtained in a) were placed in 70 ml of abs.

tBuOH under argon and treated with 5.76 g of K tert.-butylate. The mixture was cooled to about 150C internal temperature and 4.3 ml of methyl iodide were slowly added dropwise. The mixture was stirred for a further 2 hours, poured on to ice, extracted with EtOEt, washed with water and NaC1 soln., dried and evaporated. Flash chromatography on silica gel (hexane/AcOEt 96/4) yields 3.24 g of a-methylated aldehyde as a colourless oil.

c) This 3.24 g of 8-bromo-5-methyl-2,3,4,5-tetrahydro-l-benzothiepinewere placed in 45 ml of diethylene glycol and treated with 1.38 ml of hydrazine hydrate and 3.23 g of KOH pellets. The mixture was heated, firstly to 1000C for 1 hour and subsequently to 1800C for 3 hours.

After cooling the mixture was poured on to ice, extracted with EtOEt, washed with water, dried and evaporated i.v. Flash chromatography on silica gel (hexane) gave 2.58 g of 8-bromo-5,5-dimethyl-2,3,4,5-tetrahydro- 1-benzothiepine as colourless crystals, m.p. 81-820C.

d) 2.54 g of the above bromide were placed in 30 ml of abs. THF under argon and converted into the corresponding Li compound at -780C by the dropwise addition of 6.3 ml of 1.5M nBuLi. After 30 minutes 2.9 ml of anhydrous nitrobenzene were added thereto at -780C. After 1 hour the mixture was poured on to ice, extracted with EtOEt, washed with water, dried and evaporated. Flash chromatography on silica gel I (hexane/AcOEt, 95:5) yielded 1.08 g of 5,5-dimethyl-2,3,4,5-tetrahydro-1benzothiepin-8-ol as a brownish oil.

y" S" e) 340 mg of NaH (about 50%) were placed in 10 ml of abs. DMF under argon. 1.08 g of 5,5-dimethyl-2,3,4,5-tetrahydro-l-benzothiepin-8ol dissolved in 10 ml of abs. DMF were added dropwise thereto at OOC and the mixture was stirred for 30 minutes. Then, 1.36 g of 1-octyl bromide were added and the mixture was left to react at room temperature for 2 hours. The mixture was poured on to ice, extracted with EtOEt, washed with water, dried and evaporated. Flash chromatography on r B' 'N V1 -16silica gel (hexane/AcOEt =99/1) yielded 1.60 g of 5,5-dlmethyl-8-octyloxy- 2,3 ,4,5-tetrahydro- 1-benzothiepine as a colourless oil.

0l 0.86 nil of AcCi and 1.24 g of AIC1 3 were placed in 17 ml of CH 2 Cl 2 tinder argon. 1.60 g of 5 ,5-dimethyl-8-octyloxy-2,3 ,4,5-tetrahydro- 1benzothiepine dissolved in 15 ml of CH 2 Cl 2 were added dropwise thereto at -200C. After 15 minutes the mixture was poured on to ice, extracted with EtOEt, washed with bicarbonate and NaCl solution, dried and evaporated. Flash chromatography on silica gel (hexane/AcOEt 95/5) yielded 1.97 g of 1-(5,5-dimethyl-8-octyloxy-2,3,4,5-tetrahydro-1benzoth-iepin-7-yl)-ethanone as a colourless oil.

g) 1.93 g of l-(5,5-dimethyl-8-octyloxy-2,3,4,5-tetrahydro- 1benzotbiepin-7-yl)-ethanone were placed in 40 ml of CH 2 Cl 2 and treated at -250C with 3.81 g of m-chloroperbenzoic acid (about The mixture was stirred at OOC for 2.5 hours, poured on to ice, extracted with AcOlEt, washed in succession with pyrosuiphite soln., 2N NaOH, water and NaCl soln., dried and evaporated. Flash chromatography on silica gel (hexane/AcOEt 8/2) gave 1.77 g of l-(l,-dioxo-5,5-climethyl-8-octyloxy- 2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-ethancne as a colourless oil.

h) 1.77 g of 1, 1-dioxo-5,5-dimethyl-8-octyloxy-2,3 ,4,5-tetrahydro- 1benzothiepmn-7-yl)-ethanone were dissolved in 15 ml of EtOH and treated with 1.68 mg of NaBH 4 After 2 hours the mixture was poured on to ice, extracted with AcOEt, washed with water, dried and evaporated. There were thus obtained 1.84 g of l.-(l,l-dioxo-5,5-dimethyl-8-octyloxy-2,3,4,5tetrahydro-1-benzothiepin-7-yl)-ethanol as a colourless oil which was uniform according to TLC.

Example If In analogy to Example 9 there were manufactured: 1k.- temperature range lying between 00 and the boiling point of the reaction mixture.

TAA

17 methyl (E)-4-[2-(8-heptyloxy-5 ,5-dimethyl-1 -dioxo-2 ,3,4 tetrahydro- I1-benzothiepin-7 -yl )-propenyl] -benzo ate as white crystals, m.p. 92-931C.

Eap 193 nag of methyl (E)-4-12-(8-heptyloxy-5 ,5-dimethyl- 1,1 -dioxo- 2,3,4,5-tetrahydro- 1-benzothiepin-7-yl)-propenyl]-benzoate were placed in 2 ml of THF/EtOH and treated with 0.37 ml of 3N NaOH. The mixture was stirred at room temperature overnight, poured on to ice, extracted with AcOEt, washed with a small amount of water, dried and evaporated i.v. Crystallization from AcOEt yielded 152 mg of ,5-dimethyl- 1, 1-cioxo-2,3 ,4,5-tetrahydro- 1-benzothiepin-7-yl propenyl]-benzoic acid as white crystals, m.p. 153-1540C.

Examule 12 In analogy to Example 11 there were manufactured: (E)-4-[2-(8-octyloxy-5 ,5-dimethyl- 1, 1-dioxo-2,3 ,4,5-tetrahydro- 1benzothiepin-7-yl)-propenylU-benzoic acid as white crystals, m.p. 168- 169 0

C.

Example 13 3.58 g of 1-(5,5-dimethyl-8-octyi-1,1-dioxo-2,3,4,5-tetrahydro-1benzothiepin-7-yl)-ethanol were placed in 20 ml of acetonitrile and treated with 3.34 g of triphenylphosphine hydrobromide. The mixture was heated under reflmx for 70 hours, cooled and evaporated i.v. The residue was taken, up in CH 2 Cl 2 dried over Na2SO 4 and again evaporated. Trituration -in 200 ml of EtOEt/hexane finally yielded 5.67 g of phosphonium. salIt as white crystals. This phosphoniurn salt was dissolved in 80 ml of abs. ITHE under argon and deprotenized at OOC I rl by the dropwise addition of 7.45 ml of 1.55M nBuLi. After 15 minutes L uI-uIIrmore, tne compounds of formula I can be used for the treatment and prevention of disease states which can be caused by an over-regulation of the RARa-receptor. There come into consideration in this connection autoimmune diseases or other disorders having a strong -18- 1.60 g of methyl 4-formylbenzoate were added thereto and the mixture was left to react at room temperature for 1 hour. Extraction with AcOEt, washing with water, drying, evaporation, flash chromatography on silica gel (hexane/AcOEt 80/20) and two-fold recrystallization from hexane/AcOEt finally gave 1.41 g of methyl (E)-4-[2-(5,5-dimethyl-8-octyl- 1,1-dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-propenyl]-benzoate as white crystals, m.p. 85-860C.

The 1-(5,5-dimethyl-8-octyl-1,1-dioxo-2,3,4,5-tetrahydro- 1-benzothiepin-7-yl)-ethano used as the starting material was prepared as follows: a) The corresponding Grignard compound was prepared from 3.00 g of 8-bromo-5,5-dimethy1-2,3,4,5-tetrahydro-1-benzothiepine and 340 mg of Mg shavings in 30 ml of abs. THF under argon. After cooling to -200C there were added thereto 220 mg of purified CuI followed by 3.18 ml of 1iodooctane. The mixture was warmed to OOC and, after 1.5 hours, poured into ice/NH 4 C1 solution. Extraction with EtOEt, washing with water and NaC1 solution, drying, evaporation and flash 2o chromatography on silica gel (hexane) yielded 2.56 g of 5,5-dimethyl-8octyl-2,3,4,5-tetrahydro- 1-benzothiepine as a colourless oil.

b) As described under Example 9f), g) and this 5,5-dimethyl-8octyl-2,3,4,5-tetrahydro-1-benzothiepine was acetylated, oxidized to the sulphone and finally reduced with NaBH 4 to 1-(5,5-dimethyl-8-octyl-1,1dioxo-2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-ethanol.

Example 14 o 30 In analogy to Example 11 there was manufactured: (E)-4-[2-(5,5-Dimethyl-8-octyl- 1.1-dioxo-2,3,4,5-tetrahydro-1benzothiepin-7-yl)-propenyl-benzoic acid as white crystals, m.p. 164- 165 0

C.

tocopheramine as well as butylated hydroxyanisole or butylated hydroxytoluene, can be admixed with the preparations.

a -19 Example 15 (Reference Example)

A.

a) 2.20 g of 1-(5,5-dimethyl-8-hexyloxy-2,3,4,5-tetrahydro-1benzothiepin-7-yl)-ethanone, prepared in analogy to Example 9f), were placed in 20 ml of abs. THF under argon and treated at -200C with 9.9 ml of 1M vinylmagnesium bromide solution (THF). After completion of the addition (clearly exothermic) the mixture was left to react for 1 hour and then poured on to ice/NH 4 C1. Extraction with EtOEt, washing with saturated NaCI solution, drying and evaporation followed by flash chromatography on silica gel (hexaneAcOEt 95/5) gave 2.16 g of tertiary alcohol as a colourless oil.

b) The foregoing alcohol was dissolved in 15 ml of acetonitrile and treated with 2.45 g of triphenylphosphine hydrobromide. The mixture was stirred at room temperature overnight, the solvent was removed i.v.

and the residue was taken up in CH 2 C12. Drying, evaporation and digestion in 200 ml of EtOEt/ hexane 1/1 yielded 4.14 g of rearranged phosphonium salt as a pink solid.

S 20 c) 4.14 g of the phosphonium salt were placed in 20 ml of 1,2-butylene oxide and treated with 691 mg of ethyl (E)-3-formyl-crotonate. The mixture was heated to reflux for 1 hour, cooled, poured on to ice and extracted with EtOEt. Washing with water and saturated NaC1 solution drying, evaporation and flash chromatography on silica gel (hexane/AcOEt 96/4) yielded 2.58 g of triene ester which was isomerized largely to the all-trans compound as follows: d) 2.58 g of the reiene ester were dissolved in 25 ml of acetonitrile under argon and 37 mg of Pd(II) nitrate, 134 mg of triphenylphosphine and 35 microlitres of triethylamine were added thereto. The mixture was stirred at 500C for 4 hours and worked up. Renewed flash chromatography on silica gel (hexane AcOEt 96/4) yielded 2.33 g of almost isomer-pure ethyl (2E,4E,6E)-7-(8-hexyloxy-5,5-dimethyl-2,3,4,5tetrahydro-l-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoate as a pale yellow oil which was oxidized to the sulphone as follows: e) The ester was placed in 75 ml of CH 2 C12 and the solution was treated at -200C with 2.4 eq. of m-chloroperbenzoic acid. The mixture dropwise at OOC with a solution of 77 g of S-(3-heptyloxyphenyl)dimethylthiocarbamate in 200 ml of THF. After stirring at room temperature for 1 hour a solution of 46.5 g of 3,3-dimethylallyl bromide

I:

20 was allowed to warm to OOC and the reaction was followed by thin-layer chromatography. After 2 hours the mixture was poured on to ice, extracted with AcOEt, washed in succession with Na pyrosulphite solution, 2N NaOH and NaCl solution, dried and evaporated. Medium pressure chromatography on silica gel (hexane/AcOEt 85/15) followed by recrystallization from hexane/AcOEt finally yielded 760 mg of ethyl (2E,4E,6E)-7-(8-hexyloxy-5,5-dimethyl- 1,1-dioxo-2,3,4,5-tetrahydro-1benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoate as colourless crystals of melting point 116-1200C Moreover, 170 mg of the over-oxidized 6,7epoxy derivative were obtained.

B. In analogy to a) e) there was manufactured: Ethyl (2E,4E,6E)-7-(8-heptyloxy-5,5-dimethyl-1,1-dioxo-2,3,4,5tetrahydro- 1-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoate as pale yellow crystals of m.p. 98-99 0

C.

Example 16 254 mg of ethyl (2E,4E,6E)-7-(8- heptyloxy-5,5-dimethyl-1 1-dioxo- 2,3,4,5-tetrahydro-1-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoate were placed in 2 ml of EtOHTHF 1/1 and treated with 0.5 ml of 3N NaOH.

The mixture was stirred overnight, poured on to ice, acidified with cone.

HC1, extracted with AcOEt, washed with a small amount of water, dried and evaporated i.v. Crystallization from AcOEt/hexane yielded (2E,4E,6E)-7-(8-Heptyloxy-5,5-dimethyl- 1,1-dioxo-2,3,4,5tetrahydro- 1-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoic acid as pale yellow crystals of m.p. 152-153 0

C.

I-

or m-chloroperbenzoic acid in 120 ml of chloroform were added dropwise. The reaction mixture was stirred at OOC overnight, poured into ice-water/dilute sodium chloride solution and extracted with

V

-21- Example 17 In analogy to Example 15A there was manufactured: Ethyl (2E,4E,6E)-7-(5,5-dimethyl-1, 1-dioxo-2,3,4,5-tetrahydro-8octyl- 1-benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoate as colourless crystals of m.p. 88-89 0

C.

Example 18 In analogy to Example 16 there was manufactured: (2E,4E,6E)-7-(5,5-Dimethyl-1,1-dioxo-2,3,4,5-tetrahydro-8-octyl-1benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoic acid as pale yellow crystals of m.p. 104-105 0

C.

iExamle 19 In analogy to Example 9 there was manufactured: Methyl (E)-4-[2-(6-heptyloxy-3,3-dimethyl-1,1-dioxo-2,3-dihydroas white crystals of m.p. 960C.

The 6-bromo-3,3-dimethyl-2,3-dihydrobenzo[bjthiophene used as the starting material was synthesized as follows: 17.08 g of 3-bromothiophenol were placed in 60 ml of acetone and treated at OOC with 37.3 g of powdered K 2 C0 3 Then, 10.1 ml of ethyl bromoacetate were slowly added dropwise thereto and the mixture was left to react for 1 hour. Subsequently, the mixture was poured on to ice, extracted with EtOEt, washed with water, dried over Na 2

SO

4 and evaporated. There were thus obtained 24.05 g of product (GC which was processed as follows: The corresponding Grignard compound was prepared from 5.46 g of Mg shavings and 14.5 ml of Mel in 150 ml of abs. EtOEt under argon

I-

phase, eluent hixane/THF 9:1 0.1% acetic acid) there were obtained, after recrystallization from AcOEt/hexane, 4.1 g of dihydro-4',4'-dimethyl-7'-(heptyloxy)-2'H-1-benzothiopyran- 6 .i -22 according to the standard procedure. 22.8 g of the ester prepared above, dissolved in 70 ml of abs. EtOEt, were added dropwise thereto at -100C.

After 1 hour the mixture was poured on to ice/NH 4 C1, extracted with EtOEt, washed with sat. NaCI solution, dried over Na2SO 4 and evaporated. Flash chromatography on silica gel (hexane/AcOEt 85/15) gave 11.94 g of tertiary alcohol which was cyclized as follows: 21.7 g of AIC1 3 were placed in 80 ml of CS 2 under argon. 11.94 g of the tertiary alcohol prepared above, dissolved in 10 ml of CS 2 were added dropwise at OOC while stirring. The mixture was heated to reflux for 3 hours, cooled, poured cautiously on to ice and extracted with hexane.

The organic phase was washed with water, dried over Na 2

SO

4 and the solvent was removed i.v. Flash chromatography on silica gel (hexane) yielded 9.54 g of a mixture which according to GC contained 36.5% of the desired 6-bromo-3,3-dimethyl-2,3-dihydro-benzo[b]thiophene and 60% of the regioisomeric 4-bromo compound. Separation was effected at the next stage, after conversion into the corresponding phenols, which was carried out as described under Example 9d).

Example In analogy to Example 11 there was manufactured: (E)-4-[2-(6-Heptyloxy-3,3-dimethyl-1,1-dioxo-2,3-dihydrobenzo[b]thiophen-5-yl)propenyl]-benzoic acid as white crystals of m.p.

151-152 0

C.

Lu Iormyi-cruLuiinwalt 111 jvim v. reaction mixture and the mixture obtained was stirred at room temperature for a further 45 minutes. It was then poured into 500 ml of )I

I-

23 Example A Hard gelatine capsules can be produced as follows: Ingredients rneLcaY sul e Spray-dried powder containing 75% of compound I Sodium dioctylsulphosuccinate Sodium carboxymethylcellulose Microcrystalline cellulose Talc Magnesium stearate Total 0.2 4.8 86.0 120 The spray-dried powder, which is based on the active ingredient, gelatine and microcrystalline cellulose and which has an average particle size of the active ingredient of <1 i (measured by means of autocorrelation spectroscopy), is moistened with an aqueous solution of sodium carboxymethylcellulose and sodium dioctylsulphosuccinate and kneaded. The resulting mass is granulated, dried and sieved, and the granulate obtained is mixed with microcrystalline cellulose, talc and magnesium stearate. The powder is filled into size 0 capsules.

Example B Tablets can be produced as follows: Ingredient ma/tablet 1. Compound I as a finely milled powder 2. Powd. lactose 3. White corn starch 4. Povidone K30 White corn starch 6. Talc 7. Magnesium stearate 100 8 112 16 4 320 Total ft i p.- 24 The finely milled active ingredient is mixed with lactose and a portion of the corn starch. The mixture is moistened with an aqueous solution of Povidone K30 and kneaded, and the resulting mass is granulated, dried and sieved. The granulate is mixed with the remaining corn starch, talc and magnesium stearate and pressed to tablets of suitable size.

Example C Soft gelatine capsules can be prepared as follows: Ingredients 1. Compound I 2. Triglyceride mg/capsule 455 455 Total g of compound I are dissolved in 90 g of medium-chain triglyceride while stirring and under inert gasification and protection from light. The solution is processed as a capsule fill mass to soft gelatine capsules containing 5 mg of active ingredient.

Example D A lotion can be produced as follows: Ingredients 1. Compound I finely milled 2. Carbopol 934 3. Sodium hydroxide 4. Ethanol, 94% Demineralized water 1.0 g 0.6 g q.s. ad pH 6 50.0 g ad 100.0 g The active ingredient is incorporated into the 94% ethanol/water mixture with protection from light. Carbopol 934 is stirred in until gelling is complete and the pH value is adjusted with sodium hydroxide.

Claims

1. Compounds of the formula in which X represents -SO- or -SO 2 R1 represents C 7 1 -alkyl or C7..lo-alkoxy; R 2 represents a residue of the formula R 3 R 3 represents carboxy or lower-alkoxycarbonyl; and n represents 1, 2 or 3; and salts of carboxylic acids of formula T.

2. Compounds a( -tording to claim 1, in which RI is heptyl, octyl, heptyloxy or octyloxy.

3. Compounds according to claim 1 or claim 2, in which X SO 2

4. is carboxyl. Compounds according to any one of claims 1-3, in which R 3

5. Compounds according to any one of claims 1-4, in which R 2 is a residue of formula

6. Ethyl (all-E)-7-[7-heptyloxy-3 ,4-dihydro-4,4-dimethyl-2H- 1- benzothiopyran-6-yl-3-methyl-octa- 2 ,4,6-trienoate, (all-E)-7-[7-heptyloxy-3 ,4-dihydro-4,4-dimethyl-2H- 1-benzo- thiopyran-6-yl]-3-methyl- 2 ,4,6-octatrienoic acid, I- hexane/AcOEt There were obtained 1.3 g of 6-acetyl-7-octyl-3,4- dihydro-4,4-dimethyl-2H- 1-benzothiopyran as a pale yellowish oil. -26- (all-E)-7-[7-heptyloxy- 1-oxo-3 ,4-dihydro-4,4-dimethyl-2H- 1-benzo- thiopyran-6-yl]-3-methyl-octa-2,4,6-trienoic acid, (all-E )-7-[7'-(heptyloxy)-3,4'-dihydro-4' ,4'-dimethyl-2'H- 1-benzo- thiopyran-6-yl)-3-methyl-2,4,6-octatrenojc acid 1, 1-dioxide, ethyl (2E,4E,6E)-7-(8-heptyloxy-5,5-dimethyl- 1, 1-dioxo-2,3 tetrahvdro- l-benzothi epin- 7-y)-3 -m ethvl-octa-2.4,6-trieno ate.

7. (2E,4E,6E)-7-(8-Heptyloxy-5 ,5-dimethyl- 1, 1-dioxo-2,3,4,5- tetrahydro-1-benzothiepin-7-yl)-3-methylbocte-2,4,6-tienoic acid, ethyl (2E,4E,6E)-7-(5 ,5-dimethyl- 1, -dioxo. ",3,4,5-tetrahydro-8- octyl-l-benzotiepin-7-yl)-3-methyl-octa-2,4,6..trienoate, (2E,4E,6E)-7-(5,5-dimethyl-1, l-dioxo-2,3,4,5-tetrahydro-8-octyl- 1- benzothiepin-7-yl)-3-methyl-octa-2,4,6-trienoic acid.

8. Compounds according to claims 1-4, in which R 2 is a residue of formula

9. Ethyl p-[(E,Z)-2-[3',4'-dihydro-4',4'-dimethyl-7'-(heptyloxy)- 2'H- l-benzothiopyran-6'-yllpropenyllbenzoate 1'-dioxide, 4 p-[(E)-2-[3',4'-dihydro-4',4'-dimethyl-7'-(heptyloxy)-2'H-1-benzo- thiopyran-6'-yllpropenyllbenzoic acid 1',1'-dirxide, ,4'-dihydro-4',4'-dimethyl-''(heptyloxy)-2'H-1-benzo- thiopyran-6'-yllpropenyllbenzoic acid 1',1'-dioxide, ethyl (E)4-[2-(4,4-dirnethyl-7-octyl-1,1dioxo3,4dihydro2H-1 benzothiopyran-6-yl)-propenyl]-benzoate, ethyl (Z)4-[2-(4,4-dimethyl-7-octyl- 1, 1-dioxo-3 ,4-dihydro-2H- 1- benzothiopyran-6-yl)-propenyl]-benazoate, (E ,4-dimetliyl-7-octyl- 1, 1-dioxo-3 ,4-dihydro-2H- 1- benzothiopyran-6-yl)-propenyl]-benzoic acid, methyl (E)-4-[2-(8-octyloxy-5,5-dimethyl- 1, 1-dioxo-2,3 tetrahydro- l-benzothiepin-7-yl)-propenyl]-benzoate, methyl (E)-4-[2-(8-heptyloxy-5,5-dimethyl 1, 1-dioxo-2 ,3,4,5- 1-DenzotmOpyral-b-y1)-propenfl-Oeflzolc acia in wmte crybLiUb, M114J. L I a 1780C. y -27- tetrahydro- 1-benzothi epin- 7-yl)-propenyl] -be nz oate, (E)-4-[2-(8-heptyloxy-5 ,5-dirnethyl- 1, 1-dioxo-2,3,4,5-tetrahydro- 1- benzothiepin-7-yl)-propenyl]-benzoic acid, (E)-4-[2-(8-octyloxy-5,5-dimethyl-1, 1-dioxo-2,3 5-tetrahydro- 1- berizothiepin-7-yl)-propenyl]-benzoic acid, methyl ,5-dinaethyl-8-octyl- 1,1-dioxo-2,3 ,4,5-tetrahydro- 1- benzothiepin-7-yl)-propenyl]-benzoate, (E)-4-[2-(5,5-dimethyl-8-octyl-1, 1-dioxo-2 ,3 ,4,5-tc,.'i'ahydro- 1- benzothiepin-7-yl)-propenyl]-benzoic acid.

Methyl (E-4-[2-(6-heptyloxy-3 ,3-dimethyl- 1, 1-dioxo-2 ,3- -benzoate, (E)-4-[12-(6-heptyloxy-3 ,3-dinaethyl 1-dioxo-2 ,3-dihydro-benzo[b]- acid.

11. A process for the manufacture of compounds of formula I in claim 1, which process comprises reacting a compound of the formula A I (CH 2 )n with a compound of the formula CUOR B N~ '~COOR B IV wherein R is lower-alkyl and either A is a triphenyiphosphoniuim- I temperature the mixture was poured on to ice, washed with water, dried and evaporated. Flash chromatography on silica gel (hexane/AcOEt -28 ethyl group H 3 CH-P[Q] 3 Y or dialkoxyphosphinyl ethyl group CHCH-PO(OR) 2 and B is formyl; or A is acetyl and B is a triphenylmethylphosphonium group -CH2- or a dialkoxyphosphinylmethyl group -CH 2 -PO(OR) 2 and Q is phenyl; or b) reacting a compound of the formula A'V V (CH2) 10 X R' with a compound of the formula 4: wherein either A' is a triphenylmethylphosphonium group -CH 2 -P[Q] 3 Y- i: or a dialkoxyphosphinylmethyl group -CH 2 -PO(OR) 2 and B' is formyl; or i A' is formyl and B'is a triphenylmethylphosphonium group -CH2-P[Q] 3 Y Sor a dialkoxyphosphinylmethyl group -CH 2 PO(OR: and n, Q and R have 20 the significance given above, to give a compound of formula I in which R 3 is -COOR and, if desired, saponifying the ester group -COOR and Sisolating the carboxylic acid obtained as such or as a salt; and/or oxidizing a compound of formula I obtained in which X is to a Scompound of formula I in which X is -SO- or -SO2-; in a) and b) above, being an anion.

12. Pharmaceutical preparations, containing a compound of formula I in claim 1 or salts of a carboxylic acid of formula I and usual pharmaceutical carrier materials. .washed with water, dried and evaporated. Flah chromatograL l -JJ. on washed with water, dried and evaporated. Flash chromatography on I K a 29

13. according to A compound according to claim 1, whenever prepared by a process claim 11.

14. A method of the treatment of autoimmune diseases or diseases having a strong immunological component which comprises administering to a subject in need of such treatment a therapeutically effective amount of at least one compound of the formula or salts of a carboxylic acid of formula optionally in association with one or more pharmaceutically acceptable carriers.

A compound according to claim 1 substantially as herein described with reference to any one of the foregoing examples thereof.

16. A process according to claim 11 substantially as herein described with reference to any one of the foregoing examples thereof DATED this 6th day of December, 1995. F HOFFMANN-LA ROCHE AG By Its Patent Attorneys DAVIES COLLISON CAVE p:\wpdocs\grs\465748\jgs r -cI I r- I 1 1 RAN 4060-162 Abstract Compounds of the formula in which X represents -SO- or -SO 2 R 1 represents C 7 10 -alkyl or C7-1o-alkoxy; R 2 represents a residue of the formula R 3 R 3 represents carboxy or lower-alkoxycarbonyl; and n represents 1, 2 or 3; and salts of carboxylic acids of formula I can be used as medicaments, e.g. for the treatment of autoimmune diseases and diseases having a strong immunological component, such as psoriasis.